Abstract A021: Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma
Authors: Gabrielle Robbins, Kenta Yamomoto, Walker Lahr, Joseph Skeate
Journal: Clinical Cancer Research (2022)

Abstract Over the last decade, Chimeric Antigen Receptor based T cell (CAR-T) therapy has developed into an effective immunotherapy for several cancers, primarily limited to those of hematological origin. In other cancers, especially solid tumors, CAR-T cell therapies have several shortcomings and clinical success has been underwhelming. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells can mediate the direct killing of transformed cells with reduced or absent MHC expression in addition to carrying out antibody dependent cell mediated cytotoxicity (ADCC) of cells bound by antibodies via the NK cell CD16A receptor. Engineering NK cells to express CARs will effectively enable them with additional antigen specific killing. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion or persistence, and suppression by the tumor microenvironment. NK cells activated and expanded with engineered feeder cells expressing membrane bound interleukin-21 (mbIL-21) and 4-1BBL have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded CAR-NK cells that have been genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over forty years. Our proposed objective is to evaluate the non-viral KI of several CARs, either alone or in combination, that optimally activate NK cell antigen-specific killing. Genetically engineered CAR-NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that CAR-NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered CAR-NK cells. Citation Format: Gabrielle Robbins, Kenta Yamomoto, Walker Lahr, Joseph Skeate. Chimeric antigen receptor armored natural killer cell immunotherapy for osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A021.